Tomoelastography and Pancreatic Extracellular Volume Fraction Derived From MRI for Predicting Clinically Relevant Postoperative Pancreatic Fistula.

BACKGROUND: Pancreatic stiffness and extracellular volume fraction (ECV) are potential imaging biomarkers for pancreatic fibrosis. Clinically relevant postoperative fistula (CR-POPF) is one of the most severe complications after pancreaticoduodenectomy. Which imaging biomarker performs better for predicting the risk of CR-POPF remains unknown. PURPOSE: To evaluate the diagnostic performance of ECV and tomoelastography-derived pancreatic stiffness for predicting the risk of CR-POPF in patients undergoing pancreaticoduodenectomy. STUDY TYPE: Prospective. POPULATION: Eighty patients who underwent multiparametric pancreatic MRI before pancreaticoduodenectomy, among whom 16 developed CR-POPF and 64 did not. FIELD STRENGTH/SEQUENCE: 3 T/tomoelastography and precontrast and postcontrast T1 mapping of the pancreas. ASSESSMENT: Pancreatic stiffness was measured on the tomographic c-map, and pancreatic ECV was calculated from precontrast and postcontrast T1 maps. Pancreatic stiffness and ECV were compared with histological fibrosis grading (F0-F3). The optimal cutoff values for predicting CR-POPF were determined, and the correlation between CR-POPF and imaging parameters was evaluated. STATISTICAL TESTS: The Spearman's rank correlation and multivariate linear regression analysis was conducted. The receiver operating characteristic curve analysis and logistic regression analysis was performed. A double-sided P < 0.05 indicated a statistically significant difference. RESULTS: Pancreatic stiffness and ECV both showed a significantly positive correlation with histological pancreatic fibrosis (r = 0.73 and 0.56, respectively). Patients with advanced pancreatic fibrosis had significantly higher pancreatic stiffness and ECV compared to those with no/mild fibrosis. Pancreatic stiffness and ECV were also correlated with each other (r = 0.58). Lower pancreatic stiffness (<1.38 m/sec), lower ECV (<0.28), nondilated main pancreatic duct (<3 mm) and pathological diagnosis other than pancreatic ductal adenocarcinoma were associated with higher risk of CR-POPF at univariate analysis, and pancreatic stiffness was independently associated with CR-POPF at multivariate analysis (odds ratio: 18.59, 95% confidence interval: 4.45, 77.69). DATA CONCLUSION: Pancreatic stiffness and ECV were associated with histological fibrosis grading, and pancreatic stiffness was an independent predictor for CR-POPF. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 5.

Venous resection increases risk of chyle leak after total pancreatectomy for pancreatic tumors.

BACKGROUND: Existing research on chyle leak (CL) after pancreatic surgery is mostly focused on pancreaticoduodenectomy and lacks investigation on total pancreatectomy (TP). This study aimed to explore potential risk factors of CL and develop a predictive model for patients with pancreatic tumor undergoing TP. METHODS: This retrospective study enrolled 90 consecutive patients undergoing TP from January 2015 to December 2023 at Peking Union Medical College Hospital. According to the inclusion criteria, 79 patients were finally included in the following analysis. The LASSO regression and multivariate logistic regression analysis were performed to identify risk factors associated with CL and construct a predictive nomogram. Then, the ROC analysis, calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC) were performed to assess its discrimination, accuracy, and efficacy. Due to the small sample size, we adopted the bootstrap resampling method with 500 repetitions for validation. Lastly, we plotted and analyzed the trend of postoperative drainage volume in CL patients. RESULTS: We revealed that venous resection (OR = 4.352, 95%CI 1.404-14.04, P = 0.011) was an independent risk factor for CL after TP. Prolonged operation time (OR = 1.473, 95%CI 1.015-2.237, P = 0.052) was also associated with an increased incidence of CL. We included these two factors in our prediction model. The area under the curve (AUC) was 0.752 (95%CI 0.622-0.874) after bootstrap. The calibration curve, DCA and CIC showed great accuracy and clinical benefit of our nomogram. In patients with CL, the mean drainage volume was significantly higher in venous resection group and grade B CL group. CONCLUSION: Venous resection was an independent risk factor for chyle leak after TP. Patients undergoing vascular resection during TP should be alert for the occurrence of CL after surgery. We then constructed a nomogram consisted of venous resection and operation time to predict the odds of CL in patients undergoing TP.

Long-term Survival, Quality of Life, and Molecular Features of the Patients With Solid Pseudopapillary Neoplasm of the Pancreas: A Retrospective Study of 454 Cases.

OBJECTIVE: To present comprehensive information on the clinicopathological, molecular, survival characteristics, and quality of life (QOL) after surgery for solid pseudopapillary neoplasm (SPN) of the pancreas in a large cohort after long-term follow-up. BACKGROUND: SPN is a rare tumor with an uncertain malignant potential, and solid information on long-term prognosis and QOL remains limited. METHODS: All hospitalized patients with SPNs who underwent surgery between 2001 and 2021 at the Peking Union Medical College Hospital were retrospectively reviewed. The clinicopathological characteristics of the patients were retrieved. A cross-sectional telephone questionnaire was administered to inquire about the QOL. Molecular analyses were performed using whole-exome sequencing. RESULTS: Exactly 454 patients with SPN were enrolled, of whom 18.5% were males and 81.5% were females. The mean patient age was 31 ± 12 years. In total, 61.3% of the patients had no symptoms. The size of the tumors was 5.38 ± 3.70 cm; 83.4% were solid cystic tumors, and 40.1% had calcifications. The proportions of local resection, distal pancreatectomy with or without splenectomy, and pancreaticoduodenectomy with or without pylorus preservation were 29.7%, 28.9% or 22.9%, and 11% or 6.8%, respectively. Over the years, there has been a significant shift from open to minimally invasive surgery. Among all surgical procedures, pylorus-preserving pancreaticoduodenectomy (PPPD) had the highest incidence of grade 2 to 4 complications (up to 32.3%), compared with 6.7% in distal pancreatectomy ( P < 0.001). Regarding histopathology, tissue invasion, perineural invasion, cancerous microvascular emboli, lymph node metastasis, and distant metastasis were present in 16.5%, 2.2%, 0.7%, 2.0%, and 3.1% of patients, respectively. Sixty patients were lost to follow-up. Sixteen of the 390 patients who underwent resection (4.1%) experienced local recurrence or distant metastasis after surgery. In total, 361 patients responded to the telephone survey. Nearly 80% of patients claimed their QOL was not significantly affected after surgery; however, the remaining 20% complained of lower QOL during 3 to 6 years of follow-up after surgery. No clinicopathological factor could reliably predict clinical recurrence or metastasis after resection. A total of 28 driver genes were detected with mutations in at least 2 tumor samples and the top 3 frequently mutated genes were CTNNB1 , ATRNL1 , and MUC16 . CONCLUSIONS: This study presented the largest cohort of patients with SPN after surgery from a single center and reported the QOL of these patients. SPN is associated with extremely favorable long-term survival, even in patients with metastasis, and most patients have a good QOL after surgery.

Presumed radiological diagnosis of solid pseudopapillary tumors: do we really know what we are watching?

OBJECTIVES: Little is known about the clinicians' ability to ascertain the identity of a pancreatic lesion as solid pseudopapillary tumors (SPT)preoperatively. We led this retrospective study to figure out the disease spectrum that mimic SPT, the key features of SPT and the accuracy of CT and MRI in characterizing them. METHODS: Radiological and clinical database at a tertiary pancreatic disease center (Peking Union Medical College Hospital) was searched for patients who received CT or MRI with a presumed radiological diagnosis of SPT. Those patients' clinical information and final pathological diagnosis were collected. RESULTS: During 2018.10-2021.12, 200 patients had a presumed radiological diagnosis of SPT, and 132 of them had unambiguous pathological diagnosis. SPT were confirmed in only 63.6% (84/132), while the others had a variety of neoplastic and nonneoplastic lesions, including pancreatic neuroendocrine tumors (n = 15), pseudocysts (n = 4), mucinous cystic neoplasms (n = 4), serous cystadenomas (n = 3), neural sheath tumors (n = 3), lymphoepithelial cysts (n = 2), and several very rare pathologies (n = 17). Of note, 11.4% (15/132) of those were benign or nonneoplastic lesions, while 6.8% (9/132) were neoplasms with highly aggressive nature, or pancreatic metastases, which require systematic evaluation and staging instead of upfront surgery. Retrospective radiological analysis based on key imaging features, clinical history and laboratory findings had an improved diagnostic accuracy of 78.5% with CT and 77.8% with MRI. CONCLUSIONS: There is a broad disease spectrum mimicking SPT at CT and MRI. Key imaging features, clinical information and laboratory findings must be integrated to improve the diagnostic accuracy.

Identifying the preoperative factors predicting the surgical difficulty of robotic distal pancreatectomy.

BACKGROUND: Few studies have evaluated the preoperative factors predicting the surgical difficulty of robotic distal pancreatectomy (RDP). This study aims to explore such factors and provide guidance on the selection of suitable patients to aid surgeons lacking extensive experience in RDP. METHODS: A retrospective study was conducted on consecutive patients who underwent RDP to identify preoperative factors predicting surgical difficulty. High surgical difficulty was defined by both operation time and intraoperative estimated blood loss exceeding their median, or by conversion to laparotomy. RESULTS: A total of 161 patients were ultimately enrolled, including 51 patients with high levels of surgical difficulty. Multivariate analysis revealed that male sex [OR (95% CI): 4.07 (1.77,9.40), p = 0.001], body mass index (BMI) ≥ 25 kg/m2 OR (95% CI): 2.27 (1.03,5.00), p = 0.042], tumors located at the neck of the pancreas [OR (95% CI): 4.15 (1.49,11.56), p = 0.006] and splenic artery type B [OR (95% CI): 3.28 (1.09,9.91), p = 0.035] were independent risk factors for surgical difficulty. Regarding postoperative complications, high surgical difficulty was associated with the risk of overall complications and pancreatic fistula (grade B/C) (49.0% vs. 22.7%, p < 0.001; 39.2% vs. 19.1%, p = 0.006). CONCLUSION: Male sex, body mass index ≥ 25 kg/m2, tumor located at the neck of the pancreas and splenic artery type B are associated with a high RDP difficulty level. These factors can be used preoperatively to assess the difficulty level of surgery, to help surgeons choose patients suitable for them and ensure surgical safety.

Risk stratification of clinically relevant delayed gastric emptying after pancreaticoduodenectomy.

BACKGROUND: Delayed gastric emptying (DGE) remains one of the major complications after pancreaticoduodenectomy (PD), with discrepant reports of its contributing factors. This study aimed to develop a nomogram to identify potential predictors and predict the probability of DGE after PD. METHODS: This retrospective study enrolled 422 consecutive patients who underwent PD from January 2019 to December 2021 at our institution. The LASSO algorithm and multivariate logistic regression were performed to identify independent risk and protective factors associated with clinically relevant delayed gastric emptying (CR-DGE). A nomogram was established based on the selected variables. Then, the calibration curve, ROC curve, decision curve analysis (DCA), and clinical impact curve (CIC) were applied to evaluate the predictive performance of our model. Finally, an independent cohort of 45 consecutive patients from January 2022 to March 2022 was enrolled to further validate the nomogram. RESULTS: Among 422 patients, CR-DGE occurred in 94 patients (22.2%). A previous history of chronic gastropathy, intraoperative plasma transfusion ≥ 400 ml, end-to-side gastrointestinal anastomosis, intra-abdominal infection, incisional infection, and clinically relevant postoperative pancreatic fistula (CR-POPF) were identified as risk predictors. Minimally invasive pancreaticoduodenectomy (MIPD) was demonstrated to be a protective predictor of CR-DGE. The areas under the curve (AUCs) were 0.768 (95% CI, 0.706-0.830) in the development cohort, 0.766 (95% CI, 0.671-0.861) in the validation cohort, and 0.787 (95% CI, 0.633-0.940) in the independent cohort. Then, we built a simplified scale based on our nomogram for risk stratification. CONCLUSIONS: Our study identified seven predictors and constructed a validated nomogram that effectively predicted CR-DGE for patients who underwent PD.

Early Drain Removal is Safe in Patients With Low or Intermediate Risk of Pancreatic Fistula After Pancreaticoduodenectomy: A Multicenter, Randomized Controlled Trial.

OBJECTIVE: This multicenter randomized controlled trial was designed to test the hypothesis that early drain removal (EDR) could decrease the incidence of grade 2 to 4 complications for patients undoing pancreaticoduodenectomy (PD) with low or intermediate risk of postoperative pancreatic fistula (POPF). BACKGROUND: The safety and effects of EDR on postoperative complications after PD are still controversial. METHODS: A multicenter randomized controlled trial at 6 tertiary referral hospitals was carried out (NCT03055676). Patients who met the inclusion criteria, including drain amylase level less than 5000 U/L on postoperative day (POD) 1 and POD 3, and drain output less than 300 mL per day within 3 days after surgery, were enrolled. Patients were then randomized to the EDR group or the routine drain removal (RDR) group. In the EDR group, all drainage tubes were removed on POD3. In the RDR group, drainage tubes were removed on POD 5 or beyond. Primary outcome was the incidence of Clavien-Dindo grade 2 to 4 complications. Secondary outcomes were comprehensive complication index, grade B/C POPF, total medical expenses and postoperative in-hospital stay etc, within 90 days after surgery. RESULTS: A total of 692 patients were screened, and 312 patients were eligible for randomization. Baseline characteristics were well balanced between the 2 groups and 96.8% of these 312 patients had low or intermediate risk of POPF, according to the 10-point fistula risk score. A total of 20.5% of the patients in the EDR group suffered at least 1 grade 2 to 4 complication, versus 26.3% in the RDR group (P = 0.229). Multi-variate analysis showed older age (>65 years old) and blood transfusion were independent risk factors for grade 2 to 4 complications. The rate of grade B/C POPF was low in either group (3.8% vs 6.4%, P = 0.305). The comprehensive complication index of the 2 groups was also comparable (20.9 vs 20.9, P = 0.253). Total medical expenses were not significantly different. Postoperative in-hospital stay was clinically similar (15 days vs 16 days, P = 0.010). CONCLUSIONS: Nearly half of the patients undergoing PD met the inclusion criteria, predicting low incidence of grade B/C POPF and major complications. EDR was safe in these patients but did not significantly decrease major complications.

Noninvasive detection of pancreatic ductal adenocarcinoma using the methylation signature of circulating tumour DNA.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has the lowest overall survival rate primarily due to the late onset of symptoms and rapid progression. Reliable and accurate tests for early detection are lacking. We aimed to develop a noninvasive test for early PDAC detection by capturing the circulating tumour DNA (ctDNA) methylation signature in blood. METHODS: Genome-wide methylation profiles were generated from PDAC and nonmalignant tissues and plasma. Methylation haplotype blocks (MHBs) were examined to discover de novo PDAC markers. They were combined with multiple cancer markers and screened for PDAC classification accuracy. The most accurate markers were used to develop PDACatch, a targeted methylation sequencing assay. PDACatch was applied to additional PDAC and healthy plasma cohorts to train, validate and independently test a PDAC-discriminating classifier. Finally, the classifier was compared and integrated with carbohydrate antigen 19-9 (CA19-9) to evaluate and maximize its accuracy and utility. RESULTS: In total, 90 tissues and 546 plasma samples were collected from 232 PDAC patients, 25 chronic pancreatitis (CP) patients and 323 healthy controls. Among 223 PDAC cases with known stage information, 43/119/38/23 cases were of Stage I/II/III/IV. A total of 171 de novo PDAC-specific markers and 595 multicancer markers were screened for PDAC classification accuracy. The top 185 markers were included in PDACatch, from which a 56-marker classifier for PDAC plasma was trained, validated and independently tested. It achieved an area under the curve (AUC) of 0.91 in both the validation (31 PDAC, 26 healthy; sensitivity = 84%, specificity = 89%) and independent tests (74 PDAC, 65 healthy; sensitivity = 82%, specificity = 88%). Importantly, the PDACatch classifier detected CA19-9-negative PDAC plasma at sensitivities of 75 and 100% during the validation and independent tests, respectively. It was more sensitive than CA19-9 in detecting Stage I (sensitivity = 80 and 68%, respectively) and early-stage (Stage I-IIa) PDAC (sensitivity = 76 and 70%, respectively). A combinatorial classifier integrating PDACatch and CA19-9 outperformed (AUC=0.94) either PDACatch (0.91) or CA19-9 (0.89) alone (p < 0.001). CONCLUSIONS: The PDACatch assay demonstrated high sensitivity for early PDAC plasma, providing potential utility for noninvasive detection of early PDAC and indicating the effectiveness of methylation haplotype analyses in discovering robust cancer markers.

Evaluation of the diagnostic performance of the EFSUMB CEUS Pancreatic Applications guidelines (2017 version): a retrospective single-center analysis of 455 solid pancreatic masses.

OBJECTIVES: To explore the diagnostic performance of EFSUMB CEUS Pancreatic Applications guidelines (version 2017) before and after the addition of iso-enhancement and very fast/fast washout as supplementary diagnostic criteria for PDAC. METHODS: In this retrospective study, patients diagnosed with solid pancreatic lesions from January 2017 to December 2020 were evaluated. Pancreatic ductal adenocarcinoma (PDAC) is reported to show hypo-enhancement in all phases according to the EFSUMB guidelines. First, based on this definition, all lesions were categorized as PDAC and non-PDAC. Then, iso-enhancement and very fast/fast washout were added as supplementary diagnostic criteria, and all lesions were recategorized. The diagnostic performance was assessed in terms of the accuracy (ACC), sensitivity (SEN), specificity (SPE), positive predictive value (PPV), and negative predictive value (NPV). The reference standard consisted of histologic evaluation or composite imaging and clinical follow-up findings. RESULTS: A total of 455 nodules in 450 patients (median age, 58.37 years; 250 men) were included. The diagnostic performance using the EFSUMB CEUS guidelines for PDAC had an ACC of 69.5%, SEN of 65.4%, SPE of 84%, PPV of 93.5%, NPV of 40.6%, and ROC of 0.747. After recategorization according to the supplementary diagnostic criteria, the diagnostic performance for PDAC had an ACC of 95.8%, SEN of 99.2%, SPE of 84%, PPV of 95.7%, NPV of 96.6%, and ROC of 0.916. CONCLUSION: The EFSUMB guidelines and recommendations for pancreatic lesions can effectively identify PDAC via hypo-enhancement on CEUS. However, the diagnostic performance may be further improved by the reclassification of PDAC lesions after adding iso-enhancement and very fast/fast washout mode. KEY POINTS: • In the EFSUMB guidelines, the only diagnostic criterion for PDAC is hypo-enhancement, to which iso-enhancement and very fast/fast washout mode were added in our research. • Using hypo-enhancement/iso-enhancement with very fast/fast washout patterns as the diagnostic criteria for PDAC for solid pancreatic masses on CEUS has high diagnostic accuracy. • The blood supply pattern of PDAC can provide important information, and CEUS has unique advantages in this respect due to its real-time dynamic attenuation ability.

Risk factors and prevention of postoperative pancreatic fistula after insulinoma enucleation:a retrospective study from a high-volume center.

BACKGROUND/OBJECTIVES: Enucleation is an effective surgical method to treat pancreatic insulinoma, however, the incidence of clinically relevant postoperative pancreatic fistula (CR-POPF) is high. We aim to investigate the risk factors for CR-POPF which have not been well characterized and develop effective methods to prevent CR-POPF after enucleation. METHODS: This retrospective cohort study included 161 patients diagnosed with insulinoma from June 2016 to July 2020 in Peking Union Medical College Hospital. The risk factors for CR-POPF were evaluated and the role of prophylactic pre-operative pancreatic stent to prevent the occurrence of CR-POPF after enucleation of pancreatic insulinoma were explored. RESULTS: A cohort of 161 insulinoma cases were reviewed. The CT or MRI imaging reports could be tracked in 108 cases. A total of 96 patients underwent surgery, while 81 experienced pancreatic enucleation. Univariate and multivariate analyses showed that the distance from insulinoma to the main pancreatic duct (MPD) ≤2 mm was an independent risk factor for CR-POPF (p = 0.003, OR = 6.011, 95% Cl 1.852-19.512). The pre-operative pancreatic stent substantially reduced the incidence of CR-POPF in patients with tumor located in proximity to (distance ≤2 mm) the MPD (CR-POPF of the stented group vs the non-stented group: 37.5% vs 71.4%, p = 0.028). CONCLUSIONS: The distance from insulinoma to MPD ≤2 mm is a predictive factor for CR-POPF after enucleation. Pancreatic duct stenting may benefit patients with insulinoma in proximity to the MPD by enabling a lower CR-POPF rate, so it should be considered before the enucleation of the insulinoma in proximity to the MPD (distance ≤2 mm).

Distinguishing pancreatic cancer and autoimmune pancreatitis with in vivo tomoelastography.

OBJECTIVES: To prospectively investigate the stiffness and fluidity of pancreatic ductal adenocarcinoma (PDAC) and autoimmune pancreatitis (AIP) with tomoelastography, and to evaluate its diagnostic performance in distinguishing the two entities. METHODS: Tomoelastography provided high-resolution maps of shear wave speed (c in m/s) and phase angle (φ in rad), allowing mechanical characterization of the stiffness and fluidity properties of the pancreas. Forty patients with untreated PDAC and 33 patients with untreated AIP who underwent diagnostic pancreatic MRI at 3-T together with multifrequency MR elastography and tomoelastography data processing were prospectively enrolled. Ten healthy volunteers served as controls. Two radiologists and a technician measured pancreatic stiffness and fluidity independently. The two radiologists also independently evaluated the patients' conventional MR sequences using the following diagnostic score: 1, definitely PDAC; 2, probably PDAC; 3, indeterminate; 4, probably AIP; and 5, definitely AIP. Interobserver agreement was assessed. Stiffness and fluidity of PDAC, AIP, and healthy pancreas, as well as diagnostic performance of tomoelastography and conventional MRI, were compared. RESULTS: AIP showed significantly lower stiffness and fluidity than PDAC and significantly higher stiffness and fluidity than healthy pancreas. Pancreatic fluidity was not influenced by secondary obstructive changes. The intraclass correlation coefficient for pancreatic stiffness and fluidity by the 3 readers was near-perfect (0.951-0.979, all p < 0.001). Both stiffness and fluidity allowed distinguishing PDAC from AIP. AUCs were 0.906 for stiffness, 0.872 for fluidity, and 0.842 for conventional MRI. CONCLUSIONS: Pancreatic stiffness and fluidity both allow differentiation of PDAC and AIP with high accuracy. KEY POINTS: • AIP showed significantly lower stiffness and fluidity than PDAC and significantly higher stiffness and fluidity than healthy pancreas. • Both stiffness and fluidity allowed distinguishing PDAC from AIP. • Pancreatic fluidity could distinguish malignancy from non-malignant secondary obstructive changes.

ROBO2 hampers malignant biological behavior and predicts a better prognosis in pancreatic adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a fatalmalignant cancer with extremely poor prognosis and high mortality. Genome wide studies show that Slit/Robo signaling pathway takes a major effect in the oncogenesis and progression of pancreatic cancer. However, the function and mechanism of ROBO2 in the development of PDAC remains unclear. METHODS: In present study, we use Western blot and real-time polymerase chain reaction (RT-PCR) to detect the expression of ROBO2 in pancreatic cell lines. Cell proliferation,Transwellmigration and invasion were conducted inAsPC-1, MIA PaCa-2 and PANC-1cell lines. RNA sequencing, bioinformatics analysisand Western blot were used to explore its mechanism and potential target molecules. The expression of ROBO2 in 95 tumor tissues was detected by immunohistochemistry. RESULTS: ROBO2 expression was downregulated in PDAC cell lines and tissue samples. A high expression of ROBO2 was associated with better prognosis. Upregulation of ROBO2 inhibited PDAC cell proliferation, migration, and invasion. However, we found theoppositeresults in the ROBO2 downregulation group. In addition, the function of ROBO2 on cell proliferation was further affirmed by the animal model. Finally, the results of RNA sequencing indicated that ROBO2 partly promoted the antitumor activity by inhibiting ECM1 in PDAC. CONCLUSIONS: Our work suggests that ROBO2 inhibits tumor progression in PDAC and may serve as a predictive biomarker and therapeutic target in PDAC.

Comparison of minimal invasive versus open radical antegrade modular pancreatosplenectomy (RAMPS) for pancreatic ductal adenocarcinoma: a single center retrospective study.

INTRODUCTION: Radical antegrade modular pancreatosplenectomy (RAMPS) was proposed a decade ago with the aim to achieve higher R0 tangential margin and radical N1 lymph node resection for left-sided pancreatic adenocarcinoma (PDAC), which has been widely accepted worldwide at present. Laparoscopic RAMPS (Lap-RAMPS) has been attempted for PDAC during last several years, however, no outcomes evaluation by comparison between laparoscopic vs open RAMPS has been reported yet. MATERIALS AND METHODS: From August, 2012 to March, 2018, patients undergoing open or lap-RAMPS for the diagnosis of left-sided PDAC were reviewed from a prospective database. Patients excluded if they were related with combined organs or vessels resection, systematic metastasis as well as conversion from open RAMPS to lap RAMPS. The surgical and oncologic outcomes were compared. RESULTS: A total of 48 PDAC patients were enrolled (25 underwent lap-RAMPS and 23 underwent open-RAMPS). There were no significant differences in demographic or perioperative morbidity. In the lap-RAMPS group, R0 transection margin and retroperitoneal margin were both achieved in 23 of 25 patients (92%). In the open RAMPS group, R0 transection margin was achieved in 21 of 23 patients (91.3%), R0 retroperitoneal margin was 22 of 23 patients (95.65%). There were no differences in pathological examinations. The number of lymph node (LN) retrieved between lap-RAMPS and open- RAMPS group was not significant difference (15.84 vs 18.22; P = 0.268). Median disease-free survival (DFS) was analogous in two groups (18.11 m vs 20.00 m, P = 0.999). Median overall survival (OS) was 24.53 m in lap-RAMPS group and 28.73 m in the open-RAMPS group (P = 0.633). CONCLUSIONS: Lap-RAMPS is technically feasible, and has comparable long-term oncological outcome with open-RMAPS.

Changes in Serum Lactate Level Predict Postoperative Intra-Abdominal Infection After Pancreatic Resection.

OBJECTIVE: Postoperative intra-abdominal infection is one of the most serious complications after pancreatic resection. In this article, we investigated the relationship between serum lactate level and postoperative infection, to suggest a new predictor of potential infection risk after pancreatectomy. METHODS: A retrospective analysis of 156 patients who underwent pancreatic surgery and admitted in the intensive care unit for recovery after surgery between August 2017 and August 2019 was performed. RESULTS: The basic characteristics, preoperative information, pathological diagnoses, surgical methods, and intraoperative situations of patients in the postoperative intra-abdominal infection group (n = 52) and non-infection group (n = 104) showed no significant differences. With the same postoperative treatments and results of fluid balance, blood pressure maintenance, and laboratory tests, postoperative serum lactate level increased much higher in the infection group than non-infection group (P < 0.001), while the base excess level declined much lower (P = 0.002). Patients in the infection group needed more time to elute lactate (P < 0.001), and stayed longer in the intensive care unit after surgery (P = 0.007). The overall postoperative complications were certainly more in the infection group (P < 0.001), resulting in a longer hospitalization time (P < 0.001). CONCLUSIONS: When patients recovered smoothly from anesthesia with a stable hemodynamics situation and normal results of laboratory tests, abnormally high serum lactate level could be a predictor of postoperative intra-abdominal infection after pancreatic resection.

Radical antegrade modular pancreatosplenectomy (RAMPS) versus conventional distal pancreatosplenectomy (CDPS) for left-sided pancreatic ductal adenocarcinoma.

PURPOSE: The insufficient clearance of regional lymph nodes and unsatisfactory R0 resection rate may result in the metastasis of left-sided pancreatic ductal adenocarcinoma (PDAC) after conventional distal pancreatosplenectomy (CDPS). Radical antegrade modular pancreatosplenectomy (RAMPS) was designed to achieve R0 resection more successfully with better lymph-node clearance; however, there is still insufficient evidence of its short- and long-term results to confirm its superiority. We conducted this study to compare the efficiency of these two procedures. METHODS: The subjects of this retrospective analysis were 103 patients with left-sided PDAC who underwent either RAMPS (n = 46) or CDPS (n = 57). We assessed perioperative data and surgical information and used univariate and multivariate analyses to identify prognostic factors for survival. RESULTS: There were no significant differences in baseline data between the groups. RAMPS was associated with a significantly shorter hospital stay (12.11 days vs. 22.98 days; P < 0.001), and significantly less blood loss (451.09 ml vs. 764.04 ml, P = 0.002), as well as a significantly lower rate of blood transfusion (15.22% vs. 33.33%, P = 0.035). RAMPS and CDPS had comparable perioperative complication rates. Moreover, RAMPS achieved more effective lymph-node retrieval (17.87 vs. 10.23; P < 0.001). The RAMPS group had a higher overall survival (OS) rate (28.73 months vs. 18.30 months; P = 0.003) and a higher disease-free survival (DFS) rate (21.97 months vs. 9.40 months; P < 0.001). CONCLUSION: RAMPS achieved better survival and surgical outcomes than CDPS for patients with left-sided PDAC.

Whole-genome sequencing reveals distinct genetic bases for insulinomas and non-functional pancreatic neuroendocrine tumours: leading to a new classification system.

OBJECTIVE: Insulinomas and non-functional pancreatic neuroendocrine tumours (NF-PanNETs) have distinctive clinical presentations but share similar pathological features. Their genetic bases have not been comprehensively compared. Herein, we used whole-genome/whole-exome sequencing (WGS/WES) to identify genetic differences between insulinomas and NF-PanNETs. DESIGN: The mutational profiles and copy-number variation (CNV) patterns of 211 PanNETs, including 84 insulinomas and 127 NF-PanNETs, were obtained from WGS/WES data provided by Peking Union Medical College Hospital and the International Cancer Genome Consortium. Insulinoma RNA sequencing and immunohistochemistry data were assayed. RESULTS: PanNETs were categorised based on CNV patterns: amplification, copy neutral and deletion. Insulinomas had CNV amplifications and copy neutral and lacked CNV deletions. CNV-neutral insulinomas exhibited an elevated rate of YY1 mutations. In contrast, NF-PanNETs had all three CNV patterns, and NF-PanNETs with CNV deletions had a high rate of loss-of-function mutations of tumour suppressor genes. NF-PanNETs with CNV alterations (amplification and deletion) had an elevated risk of relapse, and additional DAXX/ATRX mutations could predict an increased relapse risk in the first 2-year period. CONCLUSION: These WGS/WES data allowed a comprehensive assessment of genetic differences between insulinomas and NF-PanNETs, reclassifying these tumours into novel molecular subtypes. We also proposed a novel relapse risk stratification system using CNV patterns and DAXX/ATRX mutations.

Mucins in pancreatic cancer: A well-established but promising family for diagnosis, prognosis and therapy.

Mucins are a family of multifunctional glycoproteins that mostly line the surface of epithelial cells in the gastrointestinal tract and exert pivotal roles in gut lubrication and protection. Pancreatic cancer is a lethal disease with poor early diagnosis, limited therapeutic effects, and high numbers of cancer-related deaths. In this review, we introduce the expression profiles of mucins in the normal pancreas, pancreatic precursor neoplasia and pancreatic cancer. Mucins in the pancreas contribute to biological processes such as the protection, lubrication and moisturization of epithelial tissues. They also participate in the carcinogenesis of pancreatic cancer and are used as diagnostic biomarkers and therapeutic targets. Herein, we discuss the important roles of mucins that lead to the lethality of pancreatic adenocarcinoma, particularly MUC1, MUC4, MUC5AC and MUC16 in disease progression, and present a comprehensive analysis of the clinical application of mucins and their promising roles in cancer treatment to gain a better understanding of the role of mucins in pancreatic cancer.

Diagnosis and Management of Intraabdominal Infection: Guidelines by the Chinese Society of Surgical Infection and Intensive Care and the Chinese College of Gastrointestinal Fistula Surgeons.

The Chinese guidelines for IAI presented here were developed by a panel that included experts from the fields of surgery, critical care, microbiology, infection control, pharmacology, and evidence-based medicine. All questions were structured in population, intervention, comparison, and outcomes format, and evidence profiles were generated. Recommendations were generated following the principles of the Grading of Recommendations Assessment, Development, and Evaluation system or Best Practice Statement (BPS), when applicable. The final guidelines include 45 graded recommendations and 17 BPSs, including the classification of disease severity, diagnosis, source control, antimicrobial therapy, microbiologic evaluation, nutritional therapy, other supportive therapies, diagnosis and management of specific IAIs, and recognition and management of source control failure. Recommendations on fluid resuscitation and organ support therapy could not be formulated and thus were not included. Accordingly, additional high-quality clinical studies should be performed in the future to address the clinicians' concerns.

Combined blockade of TGf-ß1 and GM-CSF improves chemotherapeutic effects for pancreatic cancer by modulating tumor microenvironment.

The interactions between tumor immune microenvironment (TIME) and pancreatic cancer cells can affect chemotherapeutic efficacy; however, the mechanisms still remain largely unknown. Thirty items in TIME were comprehensively screened by using tissue microarray from pancreatic cancer patients. Their expressions, interconnections and predictive roles for survival were analyzed. Twenty-one of 30 items could stratify the survival of the patients; however, multivariate analysis found that only 5 independent risk factors could predict worse survival (M2-polarized tumor-associated macrophages (TAMs), IgG4 positive cells, TGF-ß1, GM-CSF and lymphangiogenesis). They had a much higher expression levels in tumoral tissue, compared to peritumoral tissue. The Spearman analysis showed that M2-polarized TAM, TGF-ß1 and GM-CSF were positively correlated with pancreatic cancer stem cells (PCSC), angiogenesis and lymphangiogenesis. Both human and murine pancreatic cancer cells could induce M2-polarized TAM, which showed substantial roles to decease chemotherapeutic effects. After treated by gemcitabine, both human and murine pancreatic cancer cell lines expressed higher level of immune check points, PCSC markers and varieties of immunosuppressive factors; however, TGF-ß1 and GM-CSF had the highest increase. Based on the above results, TGF-ß1 and GM-CSF were proposed to be the optimal potential targets to improve chemotherapeutic effects. In immunocompetent murine models, we demonstrated that combined blockade of TGF-ß1 and GM-CSF improved the chemotherapeutic effects by inhibition of M2-polarized TAM and induction of CD8 positive T cells. This study presents a novel promising combined strategy to improve the chemotherapeutic effects for pancreatic cancer.

Impact of ischemia on sample quality of human pancreatic tissues.

BACKGROUND: Successful clinical evaluation of human tumors relies on proper handling of tissue samples to maximally preserve the cellular and metabolic states in vivo. Pancreatic samples are particularly sensitive to sample mishandling due to the abundance of digestive enzymes. We study how the duration of ischemia, in vivo and ex vivo, both of which are unavoidable lagging periods following surgical dissection, significantly impact the utility of pancreatic samples. METHODS: We systematically characterize a wide range of tissue integrity features, including histological patterns, cellular structures, DNA/RNA quality and activity of major signaling pathways in normal pancreases and pancreatic ductal adenocarcinoma (PDAC) tumor tissues from 41 patients with different ischemia. RESULTS: We reveal that tissues experiencing longer periods of ischemia exhibit significant deterioration and could potentially mislead disease diagnosis and preclinical research. Based on these analyses, we propose an optimal procedure that balances better clinical practice and high tissue sample quality. CONCLUSIONS: Our work provides a guideline for pancreatic sample handling and could have wide implications in clinical diagnosis and translational research.